Abstract Obstructive sleep apnea (OSA), a condition that affects a quarter of the Western adults, triples the risk for cardiovascular diseases and increases all-cause mortality. Intermittent hypoxia (IH) during transient cessation of breathing in OSA leads to endothelial inflammation, a key step in the initiation and progression of cardiovascular disease. However, the mechanisms that mediate IH-induced endothelial inflammation remain unclear and, consequently, no targeted therapy is available for vascular manifestations of OSA. Using endothelial cells (ECs) freshly harvested from OSA patients, we have identified impaired complement inhibition as an initial stimulus for endothelial inflammation in IH, thereby linking for the first time complement activation to vascular risk in OSA. We found that a major complement inhibitor CD59, a plasma membrane protein that inhibits the formation of the terminal complement membrane attack complex (MAC) and protects host cells from complement injury, is internalized from the EC surface in OSA patients. Consequent MAC deposition initiates endothelial inflammation in IH, as evidenced by nuclear translocation of nuclear factor-kappa B and increased expression of inflammatory cytokines. Importantly, we showed that IH does not significantly affect nuclear factor-kappa B activity and levels of pro-inflammatory cytokines in ECs in the absence of complement, suggesting that complement activation has an essential role in endothelial inflammation in OSA. Interestingly, internalization of CD59 in IH appears to be cholesterol-dependent and statins prevent MAC deposition on ECs in IH in a CD59-dependent manner, suggesting a novel therapeutic strategy to reduce vascular risk in OSA. This led us to hypothesize that IH-induced cellular cholesterol accumulation reduces complement inhibition via increased internalization of CD59 from the EC surface leading to increased MAC deposition, endothelial inflammation and dysfunction in OSA and that treatment of OSA with CPAP and/or statins reverses endothelial dysfunction by restoring complement inhibition. To accomplish this goal we propose the following 3 Specific Aims: 1) To determine whether reduced complement inhibition promotes endothelial dysfunction in OSA and whether CPAP reverses these changes, 2) To determine whether reduced complement inhibition is mediated by cholesterol accumulation in ECs in OSA and whether CPAP reverses these changes, and 3) To determine whether statins prevent endothelial dysfunction in OSA by preserving complement inhibition using randomized design. Using an innovative approach to characterize human vascular endothelium, the proposed studies may advance our understanding of vascular dysfunction in OSA and provide the basis for clinical trials of novel therapeutic strategies, such as addition of statins to the standard CPAP therapy, for preventing and/or reversing vascular risk in OSA.